Metastasis is the process by which tumor cells spread from a primary site to distant organs and establish secondary tumors. Because metastases are difficult to detect and cure, these growths are the cause of approximately 90% of cancer mortafity. To form metastases, tumor cells need invade through the surrounding tissue, intravasate into the circulation. After traveling in the circulation, surviving cells extravasate into a distant site, and establish new malignant colonies (secondary growth). A key issue in elucidating the mechanisms of tumor metastasis is the question of whether distinct genetic or epigenetic changes are required for each of the individual steps of metastasis. For this reason, it has become crucial to identify the genes and gene products responsible for programming these changes and to dissect their functions. In this proposal, a mouse mammary tumor metastasis model and a human mammary tumor model system are investigated to search for genes that function as pleiotropically acting, central regulators of the metastatic cascade. Using DNA microarray technology, we have identified several candidate genes whose expression strongly correlates with the ability to accomplish specific steps of the metastatic process. Detailed validation and characterization will be performed in both systems to understand the roles these genes play in the metastatic process. Study of these metastasis-associated genes will open up a large number of experimental avenues and allow detailed dissection of the cellular and molecular mechanisms of this multi-step process.